Blood contains a wealth of biomarkers that can be potentially used to diagnose cancer at early stages and to successfully manage its treatment. Biomarkers include circulating tumor cells (CTCs), cell-free DNA (cfDNA) and extracellular vesicles (EVs), which comprise the ?liquid biopsy? portfolio, originate from the developing primary tumor and the metastatic sites. However, the disease-associated blood-based biomarkers are rare, and the isolation of each from a ?liquid biopsy? requires different approaches. Thus, the development of new technologies that afford efficient and cost-effective isolation of each biomarker holds the key to advancing precision medicine approaches for individualized, patient-specific care, and treatment. BioFluidica has demonstrated a platform with superior performance capabilities of the isolation of CTCs using microfluidic technology. Building on this technology, the objective of this Phase I proposal is to develop a novel microfluidic platform and operational peripherals for the automated, solid phase extraction (SPE) of cfDNA. Leveraging our previous success, we will develop a SPE microfluidic chip for the efficient isolation of cell free DNA fragments from plasma (Aim 1). The microfluidic chip will be made from polycarbonate that can be molded, allowing for high-scale production at low cost. The chip will be designed to accommodate pipette tips associated with an FDA-compliant liquid handling station to automate operation of the chip (Aim 2). We will demonstrate the utility of our microfluidic chip by enriching cfDNA isolated from plasma spiked with cfDNA containing mutant alleles of several oncogenes ranging from 0.1-5%. Enriched cfDNA will be analyzed by a highly sensitive ligase detection reaction. The final SPE product will enrich cfDNA with high recovery and reproducibility, provide high specificity and high-throughput, and be an automated, cost-effective, and commercially viable technology.